It is generally believed that the etiology of non-insulin-dependent diabetes mellitus (NIDDM or Type II DM) is multifactorial. In general terms, the development of NIDDM is thought to occur as a result of the interaction of multiple environmental and genetic factors. Persons with NIDDM, and those predisposed to NIDDM commonly, though not universally have impaired insulin effectiveness (or insulin resistance) in vivo. There appear to be both genetic and environmental factors which account for insulin resistance. Impaired pancreatic B-cell function (diminished insulin secretion) also plays an important role in the pathogenesis of NIDDM and may also be influenced by both genetic and environmental factors. The specific genetic abnormalities which contribute to most NIDDM remain to be identified. However, in a few instances where the NIDDM has appeared at a relatively early age (usually defined as less than or equal to 25 years at diagnosis) or affected multiple family members in successive generations, specific genetic abnormalities have been found. These have included mutations in insulin receptors, the proinsulin molecule, the processing of proinsulin to insulin and in glucokinase, the enzyme that is the first link in the metabolism of glucose in the pancreatic B-cell thus contributing to the glucose signal for secretion of insulin. Although the development of hyperglycemia is the common denominator of all forms of diabetes mellitus, the standard clinical, epidemiological and clinical research tools that have been widely used to determine the pathophysiology of diabetes mellitus can be used to characterize the kind of abnormality in glucose homeostasis (phenotype) that is present in an individual or family, i.e., whether the predominate problem is one of defective insulin action, an alteration of insulin or proinsulin structure or defective insulin secretion. Depending on the nature of the specific abnormality, such studies may permit the identification of some defects in glucoregulation without the presence of overt diabetes. In this project we will carry out measurements of overnight fasting plasma glucose and insulin concentrations and studies of oral and intravenous glucose tolerance (including an index of insulin resistance) among members of families with multi generational NIDDM with onset of diabetes before 25 years of age. Families that are potentially informative for these purposes have been identified from among our Diabetes in Pregnancy Center participants and the Endocrinology and Diabetes Clinics of Children's Memorial Hospital and Northwestern Medical Faculty Foundation. If these preliminary studies suggest a distinct pattern within a given family, arrangements will be made to check for mutations in candidate genes.